1. Field of the Invention
The present invention relates to a process for lyophilizing a therapeutically-active agent in solution, and the delivery container for using the lyophilized active agent.
2. Description of the Prior Art
Lyophilization is a process which extracts liquid from a solution to form a granular solid or powder which is stable and easier to store at room temperature than the liquid. Lyophilization is carried out by freeze drying, or, more specifically, freezing followed by sublimation, which is the transition of a solid to the gaseous state without first passing through an intermediate liquid phase. Lyophilization is used instead of simply filling a container, such as a syringe, with a solid form of the active agent, because existing powder-filling equipment is incapable of filling to the precise tolerances required for some potent active agents, including various pharmaceuticals. The lyophilization process allows a larger quantity by weight of the active agent and suitable solvent to be filled in the container, thereby allowing for greater accuracy than powder-filling.
Lyophilization has many advantages compared to other drying and preserving techniques. It maintains the quality of the preserved substance, because the substance remains at a temperature that is below the freezing-point during sublimation. The resulting lyophilized matter can usually be stored without refrigeration, reducing storage and transportation costs of the substance as well as the storage space required for the product. It also reduces the weight of the lyophilized product, which similarly reduces shipping and related costs. In addition, lyophilized substances can be easily reconstituted prior to use, often in the very containers in which they were lyophilized and stored.
Lyophilization is particularly useful for preserving and storing various pharmaceuticals, because it increases their shelf-life. Moreover, the lyophilization can be performed in a syringe, and the lyophilized medication can be stored in the syringe. Diluent can then be added to the syringe for reconstitution of the medication, and the medication can be administered from the syringe to the patient.
Lyophilization has traditionally been performed in glass vials or ampules, but not syringes. Syringes, however, are the preferable means for lyophilization for active agents whose ultimate use will be from a syringe, since the active agent can be reconstituted and ultimately used in the syringe in which it was lyophilized. Lyophilization in a vial or ampule, on the other hand, requires transfer of the reconstituted active agent from the vial or ampule to the syringe. A particularly useful application for lyophilization in syringes would be for injectable pharmaceuticals.
Although lyophilization in syringes is known, as discussed and disclosed in U.S. Pat. Nos. 5,320,603, 5,184,450, 5,080,649, 4,874,381 and European Patent Application No. 0664137A2, there are problems and drawbacks with the known techniques. As discussed in U.S. Pat. No. 5,320,603, there are generally two types of syringes for lyophilization. A syringe for one-time use may be made containing lyophilized medication, to which diluent can be added to make the drug injectable. An example of such a syringe is disclosed in European Patent Application No. 0664137A2.
A second type of syringe contains two pistons, namely, a front or distal piston which separates the syringe barrel interior into two chambers, one containing the lyophilized medication and the other containing the diluent. This piston permits the bypass by axial displacement of diluent from one chamber to the other. The contents are mixed, and the second rear or proximal plunger-type piston is used to expel and dispense the reconstituted drug. Examples of this type of syringe are disclosed in U.S. Pat. Nos. 5,320,603 and 4,874,381.
As pointed out in U.S. Pat. No. 5,320,603, in both systems the syringe is prepared by filling the syringe barrel with a quantity of the medication in solvent to be lyophilized. The distal end of the syringe barrel is capped to maintain sterility. The proximal end contains a piston or plunger, which can allow the passage and escape of vapor during lyophilization. The syringe is lyophilized to drive off the vaporized solvent, which escapes through the distal end of the syringe barrel. The syringe is then ready for reconstitution with diluent prior to administration of the medication.
These disposable syringes are not readily susceptible to mass production, because they are costly to produce by the known methods. The known production methods generally require the use of many steps, special equipment, or both, as illustrated by U.S. Pat. No. 5,184,450. Regardless of the cost, current production is also difficult because of problems associated with capping the distal end of the syringe during lyophilization to preserve sterility.
In addition, although methods for lyophilization in plastic, as well as glass, syringes, is known, such as disclosed in European Patent Application No. 0664137A2A, there is no current commercial use of plastic syringes for lyophilization of medication. Glass syringes do not lend themselves as especially practical active agent delivery devices. The preferable means for administering injectable active agents, including pharmaceuticals, is by plastic syringe, which has many advantages over a glass syringe. Most notably, plastic syringes are cheaper, lighter, easier to use and safer than glass syringes.
One possible reason plastics are not being used for such commercial lyophilization is because plastics are less suitable for lyophilization containers than glass. Significantly, the thermal stresses associated with the cooling process of lyophilization limit the capability of some plastics to withstand the process, and these plastics tend to become brittle at temperatures at which glass remains intact. Consequently, lyophilization is rarely performed using plastic. It would be desirable to achieve lyophilization in plastic syringes if this problem could be overcome.
It is desired to make improvements to the known syringes and methods. It is desired to conduct lyophilization in mass produced, pre-sterilized, pre-packaged plastic syringes, which do not require any special plunger or any other unique syringe configuration to accommodate the lyophilization process. It is desired to use the same type of syringe for the lyophilization method of the present invention as is used for the administration of pharmaceuticals generally. In addition, by using a standard type of syringe, which is produced in an array of pre-sterilized and pre-packaged syringes on a plastic rack in a plastic tub, the entire tub can be put directly into a lyophilizing apparatus for lyophilization, thereby lending itself to mass production.
Moreover, whereas lyophilization is typically performed by conduction, it is desired to increase the ease and production efficiency of lyophilization by performing it by radiation, convection or both. It has not been shown that a container containing a substance to be lyophilized can be suspended within a lyophilizing apparatus, above and not in contact with any cooling surface of the lyophilizing apparatus. Lyophilization by such means would occur by radiation, convection or both. Lyophilization by radiation, convection, or both, would be easier than lyophilization by conduction, because lyophilization by the former methods is performed by simply loading a delivery container into a tub which is in turn placed into a lyophilizing apparatus. Lyophilization by conduction, however, requires manually placing the delivery container into the lyophilizing apparatus.
These and other advantages of the present invention will become apparent by referring to the detailed description of the preferred embodiment herein.
A process for lyophilizing a solution of an active agent is provided, by depositing the solution into a delivery container, covering the container with a covering plate, placing the container and covering plate inside a lyophilizing apparatus, and lyophilizing to dryness by radiation, convection or both.
A device made by this process is also provided.
Also provided is an active agent-plastic administration device, containing a single enclosed compartment, further containing an active agent in the form of lyophilized cake.
Also provided is an array of active agent-administration devices, containing an arrangement of administration devices, each having a single enclosed compartment, which compartment further contains an active agent in the form of lyophilized cake.